1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to 3-aryl-6-aryl-[1,2,4]triazolo[4,3-a]pyridines, and the use of these compounds as therapeutically effective anticancer agents.
2. Related Art
One of the hallmarks of cancer is the uncontrolled cell proliferation. Therefore, the discovery and development of antiproliferative agents which are cytotoxic to cancer cells and inhibit cancer cell growth can lead to effective treatment for cancer. Many novel chemotherapeutic agents have been discovered and developed in the past 50 years, including paclitaxel and docetaxel, doxorubicin and epirubicin, topotecan and irinotecan, cisplatin and carboplatin, as well as vincristine and vinblastine, and these cytotoxic drugs have been widely used for the treatment of both leukemia and solid tumors. More recently, significant successes have been made with targeted therapies, such as the successful development of BCR-ABL tyrosine kinase inhibitor imatinib for the treatment of chronic myeloid leukemia. However, cancer is a complex, aggressive and lethal disease. It remains a great challenge to find more effective anticancer drugs.
The mechanism of action of many current anticancer drugs frequently involves an attack at specific phases of the cell cycle to cause cell cycle arrest. In brief, the cell cycle refers to the stages through which cells progress during their lifetime. Normally, cells exist in a resting phase termed Go. During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S. Later, cell division, or mitosis occurs, in a phase called M. Antineoplastic drugs, such as vincristine, vinblastine, and paclitaxel are M phase specific.
It has been known that many cancer chemotherapeutic drugs can trigger cancer cells to undergo apoptosis. The mechanism of apoptosis involves a cascade of initiator and effector caspases that are activated sequentially. Caspases are a family of cysteine proteases that require aspartic acid residues at the P1 position of substrates for cleavage. Among these caspases, caspase-3, 6, and 7 are key effector caspases that cleave multiple protein substrates in cells, leading irreversibly to cell death. Cellular caspase activity can be measured using caspase substrates.
WO2010022076 disclosed the following triazolopyridine derivatives for use as PIM kinase inhibitors, wherein A=OR10 or NR11R12; B=H, F, Cl, OH, etc; R6=H, F, Br, Me, CN, Ph, etc.
